WO2001032127A2 - Method and compositions for treating pulmonary diseases - Google Patents

Method and compositions for treating pulmonary diseases Download PDF

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Publication number
WO2001032127A2
WO2001032127A2 PCT/US2000/030113 US0030113W WO0132127A2 WO 2001032127 A2 WO2001032127 A2 WO 2001032127A2 US 0030113 W US0030113 W US 0030113W WO 0132127 A2 WO0132127 A2 WO 0132127A2
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WO
WIPO (PCT)
Prior art keywords
pde
compounds
pde4
rolipram
asthma
Prior art date
Application number
PCT/US2000/030113
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English (en)
French (fr)
Other versions
WO2001032127A3 (en
Inventor
Peter N. Goodfellow
Richard Nieman
Theodore J. Torphy
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR0015270-6A priority Critical patent/BR0015270A/pt
Priority to JP2001534335A priority patent/JP2003513028A/ja
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EA200200518A priority patent/EA200200518A1/ru
Priority to IL14936700A priority patent/IL149367A0/xx
Priority to HU0203152A priority patent/HUP0203152A3/hu
Priority to EP00975533A priority patent/EP1225866A4/en
Priority to SK759-2002A priority patent/SK7592002A3/sk
Priority to MXPA02004350A priority patent/MXPA02004350A/es
Priority to AU13575/01A priority patent/AU1357501A/en
Priority to PL00355261A priority patent/PL355261A1/xx
Priority to DZ003225A priority patent/DZ3225A1/fr
Priority to KR1020027005609A priority patent/KR20020057988A/ko
Priority to APAP/P/2002/002496A priority patent/AP2002002496A0/en
Priority to CA002388333A priority patent/CA2388333A1/en
Publication of WO2001032127A2 publication Critical patent/WO2001032127A2/en
Publication of WO2001032127A3 publication Critical patent/WO2001032127A3/en
Priority to NO20022057A priority patent/NO20022057L/no
Priority to BG106748A priority patent/BG106748A/xx
Priority to HK02109234.5A priority patent/HK1049107A1/zh
Priority to US11/217,532 priority patent/US20060035877A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates compositions and methods for preventing or reducing the onset of symptoms of pulmonary diseases, or treating or reducing the severity of pulmonary diseases
  • compositions and methods for treating pulmonary diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor with an anti-inflammatory corticosteroid Background of the Invention
  • Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma As such, an elevation of cAMP would produce beneficial effects including 1 ) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation
  • compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells
  • the principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphod ⁇ ester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs)
  • PDE4 cyclic nucleotide phosphodiesterase
  • this invention relates to a method for treating a pulmonary disease in a mammal by administering to a patient in need thereof an effective amount of a PDE 4- specific inhibitor and an effective amount of a steroidal anti-inflammatory agent wherein the drugs are administered concomitantly together or separately and sequentially where the sequential administration is close in time or remote in time
  • this invention relates to a composition for treating a pulmonary disease in a mammal comprising an effective amount of a PDE4-spec ⁇ f ⁇ c inhibitor, an effective amount of a steroidal anti-inflammatory agent and a pharmaceutically acceptable excipient
  • the combination therapy contemplated by this invention comprises administering a
  • PDE4 inhibitor with a steroidal anti-inflammatory agent to prevent onset of a pulmonary disease event or to treat an existing condition
  • the compounds may be administered together in a single dosage form Or they may be administered as two different formulations which may be the same or different
  • both drugs may be provided separately as oral formulations, or one may be an oral preparation and the other as an inhalant, or both may be provided in an inhaled dose form They may be administered at the same time Or they may be administered either close m time or remotely, such as where one drug is administered in the morning and the second drug is administered in the evening
  • the combination may be used prophylactically or after the onset of symptoms
  • the combmat ⁇ on(s) may be used to prevent the progression of a pulmonary disease or to arrest the decline of a function, such as lung function
  • the PDE4-spec ⁇ f ⁇ c inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4.
  • PDE4 antagonists which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
  • the targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states.
  • the selective PDE 4 inhibitor rolipram which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis
  • LPDE 4 low affinity binding site
  • HPDE 4 high affinity binding site
  • yeast were transformed by known methods and the expression of recombinant PDE 4 was followed over a 6 hour fermentation period Western blot analysis using an antibody directed against PDE 4 indicated that the amount of PDE 4 expressed increased with time, reaching a maximum after 3 hour of growth.
  • greater than 90% of the immunoreactive product was in the high speed (100,000 x g) supernatant of yeast lysates H]R-(-)-Rohpram binding and PDE activity were monitored along with protein expression.
  • a further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0 1 or greater, said ratio is the ratio of the IC50 value for competing with the binding of InM of [ ⁇ 'H]R-rohpram to a form of PDE 4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 m ⁇ croM[ ⁇ H]-cAMP as the substrate
  • PDE 4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
  • Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carboxyhc acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- d ⁇ fluoromethoxyphenyl)cyclohexan- 1 -one, and /5-[4-cyano-4-(3 -cyclopropylmethoxy-4- d ⁇ fluoromethoxyphenyl)cyclohexan-l-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.
  • patent 5,552,438 issued 03 September, 1996. This patent and the compounds it discloses are incorporated herein in full by reference
  • the compound of particular interest, which is disclosed in U.S. patent 5,552,438, is -4-cyano- 4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l-carboxyhc acid and its salts, esters, pro-drugs or physical forms.
  • AWD-12-281 from Astra Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98
  • a 9-benzyladen ⁇ ne derivative nominated NCS-613 INERM
  • D-4418 from Chiroscience and Schering-Plough, a benzodiazepme PDE4 inhibitor identified as CI-1018 (PD-168787, Parke-Davis/Warner-Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766, V-l 1294A from Napp (Landells, L.J et al.
  • the steroid agents useful in this invention are oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity
  • these steroids are methyl predmsolone, prednisone, dexamethasone, fluticasone, beclomethasone, budesomde, flunisohde, mometasone furoate, and t ⁇ amcinolone acetonide
  • Methyl predmsolone and prednisone are oral and injectable forms of anti-mflammatory corticosteroids; they are available from numerous branded and generic pharmaceutical companies Beclomethasone dipropionate is sold as an aerosol for inhalation under the names Beconase® and Beconase AQ® by Glaxo Wellcome.
  • Fluticasone propionate is sold under the name Flonase® by Glaxo Wellcome as well.
  • T ⁇ amcinolone acetonide is sold by Rhone-Poulenc Roher under the name Nasacort ® as a nasal spray and aerosol.
  • Flunisohde is sold as a nasal solution under the name Nasa de® and Nasarel TM ⁇ y Roche Laboratories.
  • Dexamethasone is sold as the sodium phosphate salt by Medeva Pharmaceuticals, Inc. under the name DexacortTM Phosphate.
  • Mometasone furoate is sold as the monohydrate as a nasal preparation by Sche ⁇ ng Corp under the name Nasonex®.
  • a preferred combination therapy is that of one or more of dexamethasone, fluticasone, beclomethasone, budesomde, flunisohde, mometasone furoate, and triamcinolone acetonide administered with cts 4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-carboxyl ⁇ c acid, cilomalast (A ⁇ flo®)
  • a preferred therapy is concomitant administration of the steroid as an inhalant and the acid in an oral dose form, wherein each drug is administered once or twice a day In regards to the acid, a controlled- release oral tablet is most preferred
  • both active agents would be administered at the same time, or very close in time
  • one drug could be taken in the morning and one later in the day
  • one drug could be taken twice daily and the other once daily, either at the same time as one of the twice-a-day dosing occurred, or separately
  • both drugs would be taken together at the same time
  • the present compounds and pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules, controlled-release preparation or lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid earner for example, ethanol, peanut oil. olive oil, glycerin or water with a flavoring or colo ⁇ ng agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • examples of such earners include magnesium stearate, terra alba, talc, gelatin, acacia, stea ⁇ c acid, starch, lactose and sucrose.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrohdone, lecithin, arachis oil or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrohdone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as fluroinated hydrocarbons such as trichlorofluoromethane
  • a conventional propellant such as fluroinated hydrocarbons such as trichlorofluoromethane
  • the composition for the PDE4 inhibitors is a unit dosage form such as a tablet or capsule.
  • a metered aerosol dose, metered dry powder inhaler or nasal spray is prefe ⁇ ed
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity
  • the active ingredient is administered about once or twice a day, more preferably twice a day
  • the present compounds are useful for the treatment of exercise-induced asthma (EIA), pollution-induced asthma (PIA) and cold-induced asthma (CIA), both as chronic conditions as well as intermittently, in anticipation of the stimulus in question
  • EIA exercise-induced asthma
  • PIA pollution-induced asthma
  • CIA cold-induced asthma
  • the present compounds are used for long-term therapy
  • PDE4 inhibitors As for the amount of drug administered, it is believed that for the PDE4 inhibitors will be administered in an amount of between 1 and 200 micrograms per day per adult human. Steroids can be administered in conformity with approved labeling Example 1 — Phosphodiesterase and Rolipram Binding Assays
  • Example 1A Isolated human monocyte PDE 4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE 4 can be assessed using standard assays for PDE 4 catalytic activity employing 1 microM [ 3 H]cAMP as a substrate (Torphy et al., J. ofBiol. Chem., Vol. 267, No. 3 ppl 798-1804, 1992).
  • Rat brain high speed supernatants were used as a source of protein and both enantionmers of [->H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol.
  • Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP: 50mM Tris HC1 (pH 7.5), 5 mM MgCf?, 50 microM 5'-AMP and 1 nM of [ 3 H]-rolipram (Torphy et al., J. ofBiol. Chem., Vol. 267, No. 3 ppl 798- 1804, 1992). The assay was run for 1 hour at 30° C.
  • the reaction was terminated and bound ligand was separated from free ligand using a Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [ 3 H]- cAMP was not present.
  • the reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5-ml of cold buffer, dried, and counted via liquid scintillation spectrometry.
  • Study population Male or female patients aged between 18 and 70 years, with mild to moderate asthma, who were not adequately controlled on low doses of inhaled corticosteroids (no greater than 500 meg beclomethasone dipropionate/day or equivalent) were eligible. Patients were required to have a screening FEVi of > 50% and ⁇ 80% predicted for height, age, sex and race and a 12% or greater reversibility after beta-2 agonist administration. Patients had to have a summary symptom score of 6 or more on 4 out of 7 days preceding the baseline visit to be randomised. The sample size was
  • the primary efficacy measure was defined as the change from baseline to endpoint in trough clinic forced expiratory volume in 1 second (FEVi ). Changes in clinic FEVi were also analysed at each week of the double-blind treatment phase and over a 4-hour period immediately following the first dose of double-blind medication. Secondary efficacy variables were use of inhaled/nebulised beta-2 agonist and overnight asthma symptoms.
  • Tertiary efficacy variables were forced vital capacity (FVC), clinic peak expiratory flow rate (PEFR), forced expiratory flow at 25-75% (FEF25-75) and 75% (FEF75), domiciliary PEFR variability, domiciliary PEFR (morning and evening), summary symptom score (a composite score of overnight, morning and overall daytime asthma), morning asthma, overall daytime asthma, inhaled corticosteroid use, cough, wheeze, breathlessness/chest tightness, asthma exacerbation rates and global assessments by the physician and the patient. Study Results:
  • Corroborating support for cilomalast 15 mg BID included 4 hour FEVI, domiciliary PEFR, FEF25-75 and physician and patient global assessment scores

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/US2000/030113 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases WO2001032127A2 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
DZ003225A DZ3225A1 (fr) 1999-11-02 2000-11-01 Methode et compositions pour le traitement des maladies pulmonaires
PL00355261A PL355261A1 (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases
KR1020027005609A KR20020057988A (ko) 1999-11-02 2000-11-01 폐 질환을 치료하는 방법 및 조성물
JP2001534335A JP2003513028A (ja) 1999-11-02 2000-11-01 肺疾患を治療するための方法および組成物
HU0203152A HUP0203152A3 (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases
EP00975533A EP1225866A4 (en) 1999-11-02 2000-11-01 METHOD AND COMPOSITIONS FOR TREATING RESPIRATORY DISEASES
SK759-2002A SK7592002A3 (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases
MXPA02004350A MXPA02004350A (es) 1999-11-02 2000-11-01 Metodo y composiciones para tratar enfermedades pulmonares.
AU13575/01A AU1357501A (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases
BR0015270-6A BR0015270A (pt) 1999-11-02 2000-11-01 Método e composições para tratamento de doenças pulmonares
IL14936700A IL149367A0 (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases
EA200200518A EA200200518A1 (ru) 1999-11-02 2000-11-01 Способ и композиция для лечения заболеваний легких
APAP/P/2002/002496A AP2002002496A0 (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases.
CA002388333A CA2388333A1 (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases
NO20022057A NO20022057L (no) 1999-11-02 2002-04-30 Fremgangsmåte og sammensetning for å behandle lungesykdommer
BG106748A BG106748A (en) 1999-11-02 2002-05-29 Method and compositions for treating pulmonary diseases
HK02109234.5A HK1049107A1 (zh) 1999-11-02 2002-12-19 用於治療肺疾病的方法和組合物
US11/217,532 US20060035877A1 (en) 1999-11-02 2005-09-01 Method and compositions for treating pulmonary diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16315899P 1999-11-02 1999-11-02
US60/163,158 1999-11-02

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10129311 A-371-Of-International 2002-05-02
US10/847,223 Continuation US20040214805A1 (en) 1999-11-02 2004-05-17 Method and compositions for treating pulmonary diseases

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WO2001032127A2 true WO2001032127A2 (en) 2001-05-10
WO2001032127A3 WO2001032127A3 (en) 2001-12-06

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PCT/US2000/030113 WO2001032127A2 (en) 1999-11-02 2000-11-01 Method and compositions for treating pulmonary diseases

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EP (1) EP1225866A4 (xx)
JP (1) JP2003513028A (xx)
KR (1) KR20020057988A (xx)
CN (1) CN1387404A (xx)
AP (1) AP2002002496A0 (xx)
AR (1) AR029189A1 (xx)
AU (1) AU1357501A (xx)
BG (1) BG106748A (xx)
BR (1) BR0015270A (xx)
CA (1) CA2388333A1 (xx)
CO (1) CO5261512A1 (xx)
CZ (1) CZ20021512A3 (xx)
DZ (1) DZ3225A1 (xx)
EA (1) EA200200518A1 (xx)
EC (1) ECSP003747A (xx)
HK (1) HK1049107A1 (xx)
HU (1) HUP0203152A3 (xx)
IL (1) IL149367A0 (xx)
MA (1) MA26841A1 (xx)
MX (1) MXPA02004350A (xx)
NO (1) NO20022057L (xx)
OA (1) OA12076A (xx)
PE (1) PE20011005A1 (xx)
PL (1) PL355261A1 (xx)
SK (1) SK7592002A3 (xx)
TR (1) TR200201211T2 (xx)
TW (1) TWI242431B (xx)
WO (1) WO2001032127A2 (xx)
ZA (1) ZA200203435B (xx)

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WO2003024489A2 (en) * 2001-09-19 2003-03-27 Altana Pharma Ag Combination of a nsaid and a pde-4 inhibitor
WO2003037349A1 (en) * 2001-10-31 2003-05-08 Merck Patent Gmbh Type 4 phosphodiesterase inhibitors and uses thereof
WO2004035038A1 (ja) * 2002-10-17 2004-04-29 Ono Pharmaceutical Co., Ltd. 慢性閉塞性肺疾患治療剤
WO2004087149A1 (ja) * 2003-03-31 2004-10-14 Kyowa Hakko Kogyo Co. Ltd. 医薬組成物
JP2005539042A (ja) * 2002-08-09 2005-12-22 ヴィアトリス ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト 呼吸器疾患、アレルギー性疾患、喘息及びｃｏｐｄを処置するためのグルココルチコイド及びｐｄｅ−４−阻害剤の新規組合せ
EP1651167A2 (en) * 2003-07-31 2006-05-03 Epigenesis Pharmaceuticals LLC Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a pde-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease
WO2007045980A1 (en) * 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions of phosphodiesterase type iv inhibitors
WO2015063669A1 (en) 2013-10-30 2015-05-07 Wockhardt Limited Pharmaceutical compositions comprising combination of roflumilast and acebrophylline or pharmaceutically acceptable salts thereof
US9974909B2 (en) 2010-01-05 2018-05-22 Microdose Therapeutx, Inc. Inhalation device and method

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DE4332041C2 (de) * 1993-09-21 1997-12-11 Rentschler Arzneimittel Verwendung von Pentoxifyllin bei bestimmten Lungenerkrankungen
PE44995A1 (es) * 1994-01-27 1995-12-18 Schering Corp Furoato de mometasona para el tratamiento de las enfermedades pulmonares y de las vias respiratorias
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DATABASE CA [Online] DEPARTMENT OF PHARMACOLOGY, KING'S COLLEGE LONDON, (LONDON, ENGLAND) BANNER ET AL.: 'The effect of selective phosphodiesterase 3 and 4 isoenzyme inhibitors and established anti-asthma drugs on inflammatory cell activation', XP002938254 Retrieved from STN Database accession no. 126:14486 & BR. J. PHARMACOL. vol. 119, no. 6, 1996, pages 1255 - 1261 *
DATABASE CA [Online] INFLAMMATION BIOLOGY, THERAPEUTICS, LTD. (SLOUGH, UK) GOZZARD ET AL.: 'Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase Type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunized rabbits', XP002938255 Retrieved from STN Database accession no. 125:132083 & BR. J. PHARMACOL. vol. 118, no. 5, 1996, pages 1201 - 1208 *
See also references of EP1225866A2 *

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* Cited by examiner, † Cited by third party
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EA008108B1 (ru) * 2001-09-19 2007-04-27 Алтана Фарма Аг Комбинация нспвлс и ингибитора pde-4
WO2003024489A3 (en) * 2001-09-19 2003-09-18 Altana Pharma Ag Combination of a nsaid and a pde-4 inhibitor
WO2003024489A2 (en) * 2001-09-19 2003-03-27 Altana Pharma Ag Combination of a nsaid and a pde-4 inhibitor
US8242146B2 (en) 2001-09-19 2012-08-14 Nycomed Gmbh Combination of a NSAID and a PDE-4 inhibitor
WO2003037349A1 (en) * 2001-10-31 2003-05-08 Merck Patent Gmbh Type 4 phosphodiesterase inhibitors and uses thereof
JP2005539042A (ja) * 2002-08-09 2005-12-22 ヴィアトリス ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト 呼吸器疾患、アレルギー性疾患、喘息及びｃｏｐｄを処置するためのグルココルチコイド及びｐｄｅ−４−阻害剤の新規組合せ
WO2004035038A1 (ja) * 2002-10-17 2004-04-29 Ono Pharmaceutical Co., Ltd. 慢性閉塞性肺疾患治療剤
WO2004087149A1 (ja) * 2003-03-31 2004-10-14 Kyowa Hakko Kogyo Co. Ltd. 医薬組成物
EP1651167A2 (en) * 2003-07-31 2006-05-03 Epigenesis Pharmaceuticals LLC Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a pde-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease
EP1651167A4 (en) * 2003-07-31 2009-04-01 Epigenesis Pharmaceuticals Llc COMBINATION OF DEHYDROEPIANDROSTERONE OR DEHYDROEPIANDROSTERONE SULFATE AND A PDE-4 INHIBITOR FOR THE TREATMENT OF ASTHMA OR RESPIRATORY OBSTRUCTIVE DISEASE
WO2007045980A1 (en) * 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions of phosphodiesterase type iv inhibitors
US9974909B2 (en) 2010-01-05 2018-05-22 Microdose Therapeutx, Inc. Inhalation device and method
US10434267B2 (en) 2010-01-05 2019-10-08 Microdose Therapeutx, Inc. Inhalation device and method
WO2015063669A1 (en) 2013-10-30 2015-05-07 Wockhardt Limited Pharmaceutical compositions comprising combination of roflumilast and acebrophylline or pharmaceutically acceptable salts thereof

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JP2003513028A (ja) 2003-04-08
CO5261512A1 (es) 2003-03-31
EP1225866A2 (en) 2002-07-31
CN1387404A (zh) 2002-12-25
DZ3225A1 (fr) 2001-05-10
WO2001032127A3 (en) 2001-12-06
TR200201211T2 (tr) 2002-08-21
PL355261A1 (en) 2004-04-05
CZ20021512A3 (cs) 2003-04-16
KR20020057988A (ko) 2002-07-12
HK1049107A1 (zh) 2003-05-02
MA26841A1 (fr) 2004-12-20
IL149367A0 (en) 2002-11-10
EA200200518A1 (ru) 2002-10-31
OA12076A (en) 2006-05-04
ZA200203435B (en) 2003-06-25
TWI242431B (en) 2005-11-01
HUP0203152A3 (en) 2004-06-28
NO20022057L (no) 2002-06-27
ECSP003747A (es) 2002-05-23
BG106748A (en) 2003-02-28
SK7592002A3 (en) 2002-11-06
CA2388333A1 (en) 2001-05-10
MXPA02004350A (es) 2002-11-07
BR0015270A (pt) 2002-06-18
NO20022057D0 (no) 2002-04-30
EP1225866A4 (en) 2004-04-21
PE20011005A1 (es) 2001-09-28
AR029189A1 (es) 2003-06-18
AU1357501A (en) 2001-05-14
HUP0203152A2 (hu) 2003-01-28
AP2002002496A0 (en) 2002-06-30

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